Pyrazole derivatives and their use as cannabinoid receptor mediators

ABSTRACT

A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of: 
     
       
         
         
             
             
         
       
     
     wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl; 
     Q is H, hydroxyl, or optionally-substituted alkoxy;
         R 1 , R 2 , and R 3  are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, aralkyl, optionally-substituted thiol, or R 2  and R 3  together with Z form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring;       

     Z is B, N, —CH—, or P; 
     D is —S(O) 2 — or —C(O)—; and 
     n is 0 to 5.

This application claims the benefit of U.S. Provisional Application No. 61/991,333, filed May 9, 2014, which application is incorporated herein by reference in its entirety.

BACKGROUND

Endocannabinoids are lipid signaling molecules that act on the same cannabinoid receptors—CB₁ and CB₂—that recognize and mediate the effects of marijuana. Activation of CB₁ receptors increases appetite, increases the biosynthesis and storage of lipids, inhibits the actions of insulin and leptin, and promotes inflammation and fibrosis, which has led to the development of CB₁ receptor blocking drugs for the treatment of obesity and its metabolic complications, referred to as the metabolic syndrome. The prototype compound rimonabant proved effective in the treatment of the metabolic syndrome, but caused neuropsychiatric side effects, which resulted in its withdrawal from the market and halted further therapeutic development of this class of compounds.

SUMMARY

In one embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy;

R¹, R², and R³ are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, aralkyl, optionally-substituted thiol, or R² and R³ together with Z form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring;

Z is B, N, —CH—, or P;

D is —S(O)₂— or —C(O)—; and

n is 0 to 5.

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy; and

U is

wherein R^(a) —C(═NH)R¹, wherein R¹ is H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, or optionally-substituted phosphinyl; and R^(b) is a substituted sulfonyl or a substituted carbonyl.

Disclosed herein in a further embodiment is a compound, or a pharmaceutically acceptable salt or ester thereof, comprising (i) a CB₁ receptor mediating scaffold and (ii) a second therapeutic scaffold.

Disclosed herein in a further embodiment is a pharmaceutical composition comprising a compound disclosed herein, and at least one pharmaceutically acceptable additive.

Also disclosed herein is a composition comprising a unit dosage form of a therapeutic amount of a compound disclosed herein, and at least one pharmaceutically acceptable additive.

Disclosed herein in a further embodiment is a method for treating obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, or a co-morbidity of obesity such as arteriosclerotic heart disease or gout, in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein.

Disclosed herein in a further embodiment is a method for treating fibrosis or liver cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein.

Disclosed herein in a further embodiment is a method of preventing or reversing the deposition of adipose tissue in a subject, comprising administering to the subject in need thereof an effective amount of a compound disclosed herein.

The foregoing will become more apparent from the following detailed description of several embodiments, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts one embodiment of a general synthesis method of making the compounds disclosed herein.

FIG. 2 depicts a further embodiment of a general synthesis method of making the compounds disclosed herein.

DETAILED DESCRIPTION Terminology

The following explanations of terms and methods are provided to better describe the present compounds, compositions and methods, and to guide those of ordinary skill in the art in the practice of the present disclosure. It is also to be understood that the terminology used in the disclosure is for the purpose of describing particular embodiments and examples only and is not intended to be limiting.

“Acyl” refers to a group having the structure —C(O)R, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

“Lower acyl” groups are those that contain one to six carbon atoms. For example, an acyl group may be (C₁-C₆)alkanoyl which can be, for example acetyl, propanoyl or butanoyl.

“Acyloxy” refers to a group having the structure —OC(O)R, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. “Lower acyloxy” groups contain one to six carbon atoms. For example, an acyloxy can be a (C₂-C₆)alkanoyloxy which can be, for example, acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy.

“Administration” as used herein is inclusive of administration by another person to the subject or self-administration by the subject.

The term “aliphatic” is defined as including alkyl, alkenyl, alkynyl, halogenated alkyl and cycloalkyl groups. A “lower aliphatic” group is a branched or unbranched aliphatic group having from 1 to 10 carbon atoms.

“Alkanediyl,” “cycloalkanediyl,” “aryldiyl,” “alkanearyldiyl” refers to a divalent radical derived from aliphatic, cycloaliphatic, aryl, and alkanearyl hydrocarbons.

“Alkenyl” refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and contains one or more double bonds that may or may not be conjugated. Alkenyl groups may be unsubstituted or substituted. “Lower alkenyl” groups contain one to six carbon atoms. (C₂-C₆)alkenyl can be, for example, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl.

The term “alkoxy” refers to a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms (referred to as a “lower alkoxy”), more preferably from 1 to 4 carbon atoms, that include an oxygen atom at the point of attachment. An example of an “alkoxy group” is represented by the formula —OR, where R can be an alkyl group, optionally substituted with an alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy or heterocycloalkyl group. Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy cyclopropoxy, cyclohexyloxy, pentoxy, 3-pentoxy, or hexyloxy, and the like.

“Alkoxycarbonyl” refers to an alkoxy substituted carbonyl radical, —C(O)OR, wherein R represents an optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety. (C₁-C₆)alkoxycarbonyl can be, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl.

The term “alkyl” refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A “lower alkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 6 carbon atoms. Preferred alkyl groups have 1 to 4 carbon atoms. Alkyl groups may be “substituted alkyls” wherein one or more hydrogen atoms are substituted with a substituent such as halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl. For example, a lower alkyl or (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C₃-C₆)cycloalkyl(C₁-C₆)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl; halo(C₁-C₆)alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-tiifluoroethyl, or pentafluoroethyl; or hydroxy(C₁-C₆)alkyl can be hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, or 6-hydroxyhexyl.

“Alkynyl” refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and unless otherwise mentioned typically contains one to twelve carbon atoms, and contains one or more triple bonds. Alkynyl groups may be unsubstituted or substituted. “Lower alkynyl” groups are those that contain two to six carbon atoms. (C₂-C₆)alkynyl, for example, can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl;

The term “amine” or “amino” refers to a group of the formula —NRR′, where R and R′ can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group. For example, an “alkylamino” or “alkylated amino” refers to —NRR′, wherein at least one of R or R′ is an alkyl.

The term “aminoalkyl” refers to alkyl groups as defined above where at least one hydrogen atom is replaced with an amino group (e.g, —CH₂—NH₂).

“Aminocarbonyl” alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like. An aminocarbonyl group may be —N(R)—C(O)-R (wherein R is a substituted group or H). A suitable aminocarbonyl group is acetamido.

The term “amide” or “amido” is represented by the formula —C(O)NRR′, where R and R′ independently can be a hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group.

An “analog” is a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure or mass, such as a difference in the length of an alkyl chain or the inclusion of one of more isotopes), a molecular fragment, a structure that differs by one or more functional groups, or a change in ionization. An analog is not necessarily synthesized from the parent compound. A derivative is a molecule derived from the base structure.

An “animal” refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term “subject” includes both human and non-human subjects, including birds and non-human mammals, such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats. The term subject applies regardless of the stage in the organism's life-cycle. Thus, the term subject applies to an organism in utero or in ovo, depending on the organism (that is, whether the organism is a mammal or a bird, such as a domesticated or wild fowl).

The term “aralkyl” refers to an alkyl group wherein an aryl group is substituted for a hydrogen of the alkyl group. An example of an aralkyl group is a benzyl group.

“Aryl” refers to a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can optionally be unsubstituted or substituted. A “heteroaryl group,” is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorous. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like. The aryl or heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl or heteroaryl group can be unsubstituted.

“Aryloxy” or “heteroaryloxy” refers to a group of the formula —OAr, wherein Ar is an aryl group or a heteroaryl group, respectively.

“Carbonyl” refers to —C(O).

The term “carboxylate” or “carboxyl” refers to the group —COO⁻ or —COOH. The carboxyl group can form a carboxylic acid. “Substituted carboxyl” refers to —COOR where R is alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group. For example, a substituted carboxyl group could be a carboxylic acid ester or a salt thereof (e.g., a carboxylate).

The term “co-administration” or “co-administering” refers to administration of a compound disclosed herein with at least one other therapeutic or diagnostic agent within the same general time period, and does not require administration at the same exact moment in time (although co-administration is inclusive of administering at the same exact moment in time). Thus, co-administration may be on the same day or on different days, or in the same week or in different weeks.

The term “cycloalkyl” refers to a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term “heterocycloalkyl group” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorous.

The term “ester” refers to a carboxyl group-containing moiety having the hydrogen replaced with, for example, a C₁₋₆alkyl group (“carboxylC₁₋₆alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on. CO₂C₁₋₃alkyl groups are preferred, such as for example, methylester (CO₂Me), ethylester (CO₂Et) and propylester (CO₂Pr) and includes reverse esters thereof (e.g. —OCOMe, —OCOEt and —OCOPr).

The terms “halogenated alkyl” or “haloalkyl group” refer to an alkyl group with one or more hydrogen atoms present on these groups substituted with a halogen (F, Cl, Br, I).

The term “hydroxyl” is represented by the formula —OH.

The term “hydroxyalkyl” refers to an alkyl group that has at least one hydrogen atom substituted with a hydroxyl group. The term “alkoxyalkyl group” is defined as an alkyl group that has at least one hydrogen atom substituted with an alkoxy group described above.

“Inhibiting” refers to inhibiting the full development of a disease or condition. “Inhibiting” also refers to any quantitative or qualitative reduction in biological activity or binding, relative to a control.

“N-heterocyclic” or “N-heterocycle” refers to mono or bicyclic rings or ring systems that include at least one nitrogen heteroatom. The rings or ring systems generally include 1 to 9 carbon atoms in addition to the heteroatom(s) and may be saturated, unsaturated or aromatic (including pseudoaromatic). The term “pseudoaromatic” refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings. Aromatic includes pseudoaromatic ring systems, such as pyrrolyl rings.

Examples of 5-membered monocyclic N-heterocycles include pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), and dithiazolyl. Examples of 6-membered monocyclic N-heterocycles include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and triazinyl. The heterocycles may be optionally substituted with a broad range of substituents, and preferably with C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C₁₋₆alkyl)amino. The N-heterocyclic group may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl.

Examples of 8, 9 and 10-membered bicyclic heterocycles include 1H thieno[2,3-c]pyrazolyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, and the like. These heterocycles may be optionally substituted, for example with C₁₋₆ alkyl, C₁₋₆ alkoxy, alkenyl, C₂₋₆ alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(C₁₋₆alkyl)amino. Unless otherwise defined optionally substituted N-heterocyclics includes pyridinium salts and the N-oxide form of suitable ring nitrogens.

The term “subject” includes both human and non-human subjects, including birds and non-human mammals, such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats. The term subject applies regardless of the stage in the organism's life-cycle. Thus, the term subject applies to an organism in utero or in ovo, depending on the organism (that is, whether the organism is a mammal or a bird, such as a domesticated or wild fowl).

“Substituted” or “substitution” refers to replacement of a hydrogen atom of a molecule or an R-group with one or more additional R-groups. Unless otherwise defined, the term “optionally-substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or 3, more preferably 1 or 2 groups. The substituents may be selected, for example, from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, hydroxyl, oxo, C₁₋₆alkoxy, aryloxy, C₁₋₆alkoxyaryl, halo, C₁₋₆alkylhalo (such as CF₃ and CHF₂). C₁₋₆alkoxyhalo (such as OCF₃ and OCHF₂), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides, substituted sulfonamides, disubstituted sulfonamides, aryl, arC₁₋₆alkyl, heterocyclyl and heteroaryl wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them may be further optionally substituted. Optional substituents in the case N-heterocycles may also include but are not limited to C₁₋₆alkyl i.e. N—C₁₋₃alkyl, more preferably methyl particularly N-methyl.

“Sulfinyl” refers to the group —S(═O)H.

The term “substituted sulfinyl” or “sulfoxide” refers to a sulfinyl group having the hydrogen replaced with, for example a C₁₋₆alkyl group (“C₁₋₆alkylsulfinyl” or “C₁₋₆alkylsulfoxide”), an aryl (“arylsulfinyl”), an aralkyl (“aralkyl sulfinyl”) and so on. C₁₋₃alkylsulfinyl groups are preferred, such as for example, —SOmethyl, —SOethyl and —SOpropyl.

The term “sulfonyl” refers to the group —SO₂H.

The term “substituted sulfonyl” refers to a sulfonyl group having the hydrogen replaced with, for example a C₁₋₆alkyl group (“sulfonylC₁₋₆alkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”), a heteroaryl, a cycloalkyl, a heterocycloalkyl, and so on. SulfonylC₁₋₃alkyl groups are preferred, such as for example, —SO₂Me, —SO₂Et and —SO₂Pr.

The term “sulfonylamido” or “sulfonamide” refers to the group —SO₂NH₂.

A “therapeutically effective amount” refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat the disease or condition without causing a substantial cytotoxic effect in the subject. The therapeutically effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition.

“Thiol” refers to the group —SH.

The term “substituted thiol” refers to a thiol group having the hydrogen replaced with, for example a C₁₋₆alkyl group (“—S(C₁₋₆alkyl)”), an aryl (“—S(aryl)”), or an aralkyl (“—S(alkyl)(aryl)”) and so on. (C₁-C₆)alkylthio, for example, can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio.

“Treatment” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop, or administering a compound or composition to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing a pathology or condition, or diminishing the severity of a pathology or condition. As used herein, the term “ameliorating,” with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. The phrase “treating a disease” refers to inhibiting the full development of a disease, for example, in a subject who is at risk for a disease such as diabetes. “Preventing” a disease or condition refers to prophylactic administering a composition to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing a pathology or condition, or diminishing the severity of a pathology or condition. In certain embodiments disclosed herein, the treatment inhibits food intake or weight gain in a subject. In certain embodiments disclosed herein, the treatment inhibits fibrogenesis or reverses insulin resistance in a subject.

“Pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and/or adjuvants, and optionally other biologically active ingredients. Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (19th Edition).

The terms “pharmaceutically acceptable salt or ester” refers to salts or esters prepared by conventional means that include salts, e.g., of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. “Pharmaceutically acceptable salts” of the presently disclosed compounds also include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base. Any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof. “Pharmaceutically acceptable salts” are also inclusive of the free acid, base, and zwitterionic forms. Descriptions of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When compounds disclosed herein include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. Such salts are known to those of skill in the art. For additional examples of “pharmacologically acceptable salts,” see Berge et al., J. Pharm. Sci. 66:1 (1977).

“Pharmaceutically acceptable esters” includes those derived from compounds described herein that are modified to include a carboxyl group. An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Representative esters thus include carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl, optionally substituted by, for example, halogen, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy) or amino); sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); or amino acid esters (for example, L-valyl or L-isoleucyl). A “pharmaceutically acceptable ester” also includes inorganic esters such as mono-, di-, or tri-phosphate esters. In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group, optionally substituted as shown in the definition of carbocycylyl above. Pharmaceutically acceptable esters thus include C₁-C₂₂ fatty acid esters, such as acetyl, t-butyl or long chain straight or branched unsaturated or omega-6 monounsaturated fatty acids such as palmoyl, stearoyl and the like. Alternative aryl or heteroaryl esters include benzoyl, pyridylmethyloyl and the like any of which may be substituted, as defined in carbocyclyl above. Additional pharmaceutically acceptable esters include aliphatic L-amino acid esters such as leucyl, isoleucyl and especially valyl.

For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

The term “addition salt” as used hereinabove also comprises the solvates which the compounds described herein are able to form. Such solvates are for example hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternary ammonium salts which the compounds are able to form by reaction between a basic nitrogen of a compound and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.

Prodrugs of the disclosed compounds also are contemplated herein. A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into an active compound following administration of the prodrug to a subject. The term “prodrug” as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds described herein. Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. Prodrugs of a compounds described herein may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. F or a general discussion of prodrugs involving esters see Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard, Design of Prodrugs, Elsevier (1985).

The term “prodrug” also is intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when the prodrug is administered to a subject. Since prodrugs often have enhanced properties relative to the active agent pharmaceutical, such as, solubility and bioavailability, the compounds disclosed herein can be delivered in prodrug form. Thus, also contemplated are prodrugs of the presently disclosed compounds, methods of delivering prodrugs and compositions containing such prodrugs. Prodrugs of the disclosed compounds typically are prepared by modifying one or more functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound. Prodrugs include compounds having a phosphonate and/or amino group functionalized with any group that is cleaved in vivo to yield the corresponding amino and/or phosphonate group, respectively. Examples of prodrugs include, without limitation, compounds having an acylated amino group and/or a phosphonate ester or phosphonate amide group. In particular examples, a prodrug is a lower alkyl phosphonate ester, such as an isopropyl phosphonate ester.

Protected derivatives of the disclosed compounds also are contemplated. A variety of suitable protecting groups for use with the disclosed compounds are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.

In general, protecting groups are removed under conditions that will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. One preferred method involves the removal of an ester, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate. A second preferred method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxy-based group, including t-butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and/or methylene chloride. Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl. Other conventional protecting groups are known and suitable protecting groups can be selected by those of skill in the art in consultation with Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. When an amine is deprotected, the resulting salt can readily be neutralized to yield the free amine. Similarly, when an acid moiety, such as a phosphonic acid moiety is unveiled, the compound may be isolated as the acid compound or as a salt thereof.

Compounds

Disclosed herein are novel peripherally restricted cannabinoid receptor mediating compounds for the treatment of, for example, fibrosis, diabetes, obesity and liver cancer. The cannabinoid receptor may be CB₁ and/or CB₂ receptors. The compounds may be essentially non-selective for CB₁ versus CB₂, or show selectivity for either the CB₁ receptor or the CB₂ receptor. In a preferred embodiment, the cannabinoid receptor mediating compounds are selective of CB₁ receptors.

In certain embodiments, the cannabinoid receptor mediating compounds are cannabinoid receptor inverse agonists, particularly CB₁ inverse agonists. In certain embodiments, the cannabinoid receptor mediating compounds are neutral antagonists. A CB₁ inverse agonist is a drug that on its own produces an effect opposite to that of a CB₁ agonist, and is also able to block the effect of a CB₁ agonist. In contrast, a CB₁ neutral antagonist can only do the latter (i.e. blocking the effect of a CB₁ agonist), but has no effect on its own. CB₁ inverse agonism is usually documented by the ability of a drug to decrease GTPgammaS binding and/or to increase adenylate cyclase activity. The compounds may show functional bias for GTPgammaS or β-Arrestin or activity for both GTPgammaS and β-Arrestin.

In certain embodiments, the compounds preferentially target CB₁ receptors in peripheral tissue (e.g., adipose tissue, liver, muscle, lung, kidney, macrophages, pancreatic beta cells and gastrointestinal tract), while not interacting with CB₁ receptors in brain tissue. Peripherally-mediated effects are maintained, but CNS side effects are minimal or non-existent.

There is evidence that the metabolic effects of endocannabinoids are mediated, at least in part, by CB₁ receptors in peripheral tissues, whereas the neuropsychiatric side effects are mediated by CB₁ receptor in the brain. This suggests CB₁ receptor blocking drugs with reduced ability to penetrate the brain would cause fewer if any neuropsychiatric side effects while retaining some or most of their metabolic benefits. As to limited metabolic efficacy of CB₁ receptor blocking drugs, this could be improved by the design of dual activity compounds that act on more than one target in the cell to influence the same metabolic process. As an example, such secondary targets could include, but not limited to, the enzyme inducible nitric oxide synthase (iNOS) or adenosine monophosphate kinase (AMPK), as suggested by findings that inhibition of iNOS or activation of AMPK improves insulin resistance, and reduces fibrosis and inflammation (Shinozaki S et al., J. Biol. Chem. 2012, 286(40), 34959-34975; Young R J et al., Bioorg. Med. Chem Let. 2000, 10(6), 597-600; da Silva Morais A et al., Clin. Sci. 2010, 118(6), 411-420). Certain embodiments disclosed herein are CB₁ blocking compounds that have very low brain penetrance, and give rise to metabolites that either inhibit iNOS or activate AMPK directly.

In certain embodiments, a peripherally restricted cannabinoid CB₁ receptor mediating compound may be characterized and can be identified from a ratio of maximum concentration in the brain to maximum concentration in plasma which is less than 0.1, as measured in a mouse after intravenous dosing. The preferred peripherally restricted cannabinoid CB₁ receptor mediating compounds have a brain C_(max) to plasma C_(max) ratio which is less than 0.05. Especially preferred peripherally restricted cannabinoid receptor mediating compounds have a brain C_(max) to plasma C_(max) ratio which is less than 0.025.

In one embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy;

R¹, R², and R³ are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, aralkyl, optionally-substituted thiol, or R² and R³ together with Z form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring;

Z is B, N. —CH—, or P;

D is —S(O)₂— or —C(O)—; and

n is 0 to 5.

In certain embodiments of formula I, R² and R³ together with Z do not form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring. In certain embodiments of formula I, R² and R³ are each independently optionally-substituted alkyl (particularly lower alkyl). In certain embodiments of formula I, R² and R³ are each independently alkyl (particularly lower alkyl). In certain embodiments of formula I, R² and R³ are each the same (particularly lower alkyl). In certain embodiments of formula I, Z is N and R² and R³ together with Z do not form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring. In certain embodiments of formula I, Z is N and R² and R³ are each independently alkyl (particularly lower alkyl) or aralkyl. In certain embodiments of formula I, Z is N and R² and R³ are each the same (particularly lower alkyl). In certain embodiments of formula I, D is —S(O)₂—.

Further disclosed herein is a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein R²⁵ is an optionally-substituted N-heterocycle. In certain embodiments, the N-heterocycle of R²⁵ may be selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

In certain embodiments of formulae I or Ia, each of X and Y is optionally-substituted aryl.

Further disclosed herein is a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein each of R⁴, R¹⁰ and R¹¹ is independently selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, or optionally-substituted phosphinyl;

A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, mono or di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono or di-substituted C-aryl, mono or di-substituted C-cycloalkyl, —CH(COOR²⁰)—, —CH(CN)—. —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ is H or alkyl;

a and b are each 0 to 5; and

c is 0 to 7.

Further disclosed herein is a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

Further disclosed herein is a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy; and

U is

wherein R^(a) —C(═NH)R¹, wherein R¹ is H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, or optionally-substituted phosphinyl; and R^(b) is a substituted sulfonyl or a substituted carbonyl.

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein R², and R³ are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, or R² and R³ together with Z form an optionally-substituted cycloalkyl ring, an optionally-substituted heterocycloalkyl ring; an optionally-substituted aryl ring, or an optionally-substituted heteroaryl ring;

Z is B, N, —CH—, or P; and

n is 0 to 5.

In certain embodiments of formula IIa, R² and R³ together with Z do not form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring. In certain embodiments of formula IIa, R² and R³ are each independently optionally-substituted alkyl (particularly lower alkyl). In certain embodiments of formula IIa, R² and R³ are each independently alkyl (particularly lower alkyl). In certain embodiments of formula IIa, R² and R³ are each the same (particularly lower alkyl). In certain embodiments of formula IIa, Z is N and R² and R³ together with Z do not form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring. In certain embodiments of formula IIa, Z is N and R² and R³ are each independently alkyl (particularly lower alkyl) or aralkyl. In certain embodiments of formula IIa, Z is N and R² and R³ are each the same (particularly lower alkyl).

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein each R¹² is independently selected from optionally-substituted alkyl, optionally-substituted heteroalkyl, hydroxy, optionally-substituted alkoxy or optionally-substituted alkylamino, optionally-substituted aryl, halogen, cyano, nitro, acyl or carbonyl; and d is 0 to 5.

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein R²⁵ is an optionally-substituted N-heterocycle. In certain embodiments, the N-heterocycle of R²⁵ may be selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

In certain embodiments of formula II, IIa, IIb or IIc, each of X and Y is optionally-substituted aryl or optionally-substituted heteroaryl.

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein each of R¹³, R¹⁴ and R¹⁵ is independently selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, or optionally-substituted phosphinyl;

A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, mono or di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono or di-substituted C-aryl, mono or di-substituted C-cycloalkyl, —CH(COOR²⁰)—, —CH(CN)—, —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ is H or alkyl;

f and g are each 0 to 5; and

g is 0 to 7.

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

In a further embodiment, there is disclosed herein a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

In certain embodiments, the compounds disclosed herein may exist as a ‘NH₂’ tautomer, or a ‘NH’ tautomer, or a combination of both. For example:

Thus, also disclosed herein are the ‘NH₂’ tautomers of Formula I and Formula II (wherein the substituents are as defined above) as follows:

Formula II* wherein U is

In certain embodiments of any of the above formulae, R¹ is optionally-substituted alkyl (e.g., lower alkyl, thiol-substituted lower alkyl), aminocarbonyl (e.g., acetamido), or optionally-substituted phenyl (e.g., halogen-substituted phenyl, particularly 4-halogen-phenyl).

In certain embodiments of any of the above formulae, Q is H.

In certain embodiments of any of the above formulae, A is —CH₂—, —O—, —CH(CF₃)—, —N(alkyl)-, or mono or di-substituted C-aryl.

Particular examples of the presently disclosed compounds include one or more asymmetric centers; thus these compounds can exist in different stereoisomeric forms. Accordingly, compounds and compositions may be provided as individual pure enantiomers or as stereoisomeric mixtures, including racemic mixtures. In certain embodiments the compounds disclosed herein are synthesized in or are purified to be in substantially enantiopure form, such as in a 90% enantiomeric excess, a 95% enantiomeric excess, a 97% enantiomeric excess or even in greater than a 99% enantiomeric excess, such as in enantiopure form.

For example, compounds of formula I may be in the form of a stereoisomeric mixture or cis/trans isomers, rotamers or tautomers. In certain embodiments, the compounds of formula I may be provided as an S-enantiomer, for example, as shown below:

In certain embodiments, the agents disclosed herein are hybrid compounds that include (i) a CB₁ receptor mediating scaffold (e.g., an inverse agonist or neutral antagonist) and (ii) a second therapeutic scaffold. In certain embodiments, the —NH—C(NH)R¹— moiety or —N═C(NH2)R¹— moiety in any of the formulae disclosed herein constitutes at least a portion of the second therapeutic scaffold. In certain embodiments, the second therapeutic scaffold may undergo in vivo cleavage, thereby releasing the second therapeutic scaffold which may retain at least a portion of its therapeutic activity. For example, in the case of metformin as the second therapeutic scaffold, the resulting hybrid compound could have therapeutic efficacy not only due to its blockade of CB₁ receptors, but also due to the release of metformin, a widely used antidiabetic agent, during the in vivo metabolism of the compound. The in vivo cleavage may occur at any location in the body, but typically occurs in the liver, via the action of drug metabolizing enzymes, such as isoforms of cytochrome P450. In certain embodiments, the cleavage occurs at the bond between the —NH—C(NH)R¹— moiety or the —N═C(NH₂)R¹— moiety and the C atom of the carboximidiamide portion of the compound.

Illustrative second therapeutic scaffolds include an antidiabetic agent, an anticancer agent, an antiobesity agent, and an antifibrotic agent.

The second therapeutic scaffold is either implicit as shown below or as an explicit attachment at the unsubstituted nitrogen end:

In certain embodiments, the compounds disclosed herein have improved chemical stability resulting in a plasma half-life in the 1-16 hours range, more particularly 4-8 hours range.

In certain embodiments, the agents disclosed herein are hybrid compounds that include (i) a CB₁ receptor mediating scaffold (e.g., an inverse agonist or neutral antagonist) and (ii) a diagnostic agent or entity. In certain embodiments, the —NH—C(NH)R¹— moiety or the —N═C(NH₂)R¹— moiety in any of the formulae disclosed herein constitutes at least a portion of the diagnostic agent or entity (for example, an antibody, biotin tag, ¹⁸F, or ¹¹C-bearing group). Alternatively the diagnostic moiety for PET, SPECT imaging, autoradiography, can be obtained by replacing atoms in the X, Y or Q portion of any of the formulae yielding high affinity ligands, with radioisotopic atoms like ²H, ³H, ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁷⁵⁻⁷⁷Br, ¹²³⁻¹³¹I, or ^(99m)Tc. The diagnostic group or entity can be used in the imaging diagnosis of pathologies, like fibrosis, cancer, cardiovascular, metabolic, inflammatory and neurodegenerative diseases. The diagnostic compounds can be used as fluorescent probes, affinity labels, in nuclear medicine, optical imaging, like PET, SPECT etc. These compounds comprise a targeting CB₁ scaffold linked to at least a diagonstic signal entity. A CB₁ scaffold bearing the diagnostic entity would be capable of targeting at least one marker of a pathologic state, for example proteins, enzymes or cell receptors that are expressed in a pathologic state.

In certain embodiments, the compounds disclosed herein have low or no cytochrome P450 activity meaning that the agents may result in few, if any, drug-to-drug interactions.

In certain embodiments, the compounds disclosed herein have a CB₁R binding affinity in the range of 0.1 to 20 nM, and CB₁/CB₂selectivity of at least 20-fold, or more particularly 100-fold or greater.

FIGS. 1 and 2 depicts general synthesis methods for making the compounds disclosed herein. Synthesis Scheme I describes the general route to convert commercially available suitably substituted 2-phenylacetophenones to novel CB₁-selective inverse agonist compounds with dual activity. The synthesis procedure applies to 1,3,4-trisubstituted 4,5-dihydropyrazoles of formula I. For example, 1-(4-chlorophenyl)-2-phenylethanone can be converted to 1-(4-chlorophenyl)-2-phenylprop-2-en-1-one using 37% formaldehyde containing piperidine and acetic acid (step a). Treatment of the acrylophenone with hydrazine hydrate in refluxing 2-propanol produces 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (step b) (J. Agric. Food Chem. 1979, 27, 406).The pyrazoline was condensed with sulfonylcarbamate of the type Compound VI obtained from chlorosulfonylisocyanate(step c and d) to give the diarylpyrazoline acylsulfonamide Compound VII (step e). Chlorination of this product with phosphorus pentachloride in refluxing chlorobenzene gave the imidoylchloride Compound VIII (step f) as previously described (J. Med Che. 2004, 47, 627, and Che, Ber. 1966, 99, 2885, Bioorg Med. Chem. Lett, 2010, 20, 1752). The imidoyl chloride was coupled with compounds like acetamidine hydrochloride in the presence of triethylamine in a mixture of methanol and dichloromethane (step g) to yield 4,5-dihydro-1H-pyrazole-1-carboximidamide compounds like Compound IX. This compound can be subjected to preparative HPLC conditions using a chiral column to give R and S optically pure enantiomers. Alternatively, the racemic diarylpyrazoline acylsulfonamide can be separated on a chiral column to give optically pure enantiomeric acyl sulfonamides which can be individually subjected to further manipulations as shown in step f and g.

Synthesis Scheme II describes the general route to convert commercially available aldehydes and hydrazines to novel CB₁-selective inverse agonist compounds with dual activity. The synthesis procedure applies to 1,3,5-trisubstituted 4,5-dihydropyrazoles of formula II. The synthesis can be adapted from references Bioorg Med. Chem. Lett, 2010, 20, 1752 and/or J. Med Che. 2007, 50, 5951.Treatment of an aldehyde like benzaldehyde with pyruvic acid as in step a followed by treatment with acetyl chloride in dry ethanol (step b) affords the u43-unsaturated keto ester Compound XI. Refluxing 4-chlorophenyl hydrazine and Compound XI in a solution of ethanol and acetic acid (step c) gave the dihydropyrazole ester Compound XII. Hydrolysis of the ester in alcoholic KOH gave the coupling precursor acid Compound XIII (step d). The acid can be coupled under basic conditions using a suitably substituted phenyl sulfonamides (step e) or suitably substituted amino sulfonamides (step f) to yield acylsulfonamides of the type compound XIV and compound XV respectively. These compound each can be individually converted to the imidoyl chloride (Compounds XVI and XVII) by treatment with PCl₅ in refluxing chlorobenzene or POCl₃ treatment in presence of a base (step g). Reaction with compounds like acetamidine or SMethyl thiourea in presence of a base can yield final racemic compounds (XVIII and XIX) that can be separated by chiral HPLC to give enantiopure final compounds.

Compositions and Methods of Use

The peripherally restricted cannabinoid receptor mediating agents disclosed herein are unique in that they may improve all, or at least one, aspect(s) of the metabolic syndrome. They reduce food intake and body weight, reverse insulin and leptin resistance, reverse hepatic steatosis (fatty liver) and improve dyslipidemia. They may be used for treating obesity, diabetes (e.g., type 2 diabetes), and non-alcoholic and alcoholic fatty liver disease (NAFLD/AFLD), the latter being a risk factor for insulin resistance, cirrhosis and liver cancer, dyslipidemias that predispose to arteriosclerotic heart disease, diabetic nephropathy, gout, and fibrosis. The agents disclosed herein may be devoid of the psychiatric side effects that prevent the use of globally acting CB₁ antagonists.

The diabetes disorder may be Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, and/or insulin resistance.

Also disclosed herein is a method for treating a co-morbidity of obesity. The co-morbidity may be selected from diabetes, Metabolic Syndrome, dementia, and heart disease. In further embodiments, the co-morbidity is selected from hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous statis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arterial sclerotic disease; pseudotumor cerebri; accident proneness; increased risks with surgeries; osteoarthritis; high cholesterol; and, increased incidence of malignancies of the liver, ovaries, cervix, uterus, breasts, prostrate, and gallbladder.

Also disclosed herein is a method of preventing or reversing the deposition of adipose tissue in a subject. By preventing or reversing the deposition of adipose tissue, the compounds disclosed herein are expected to reduce the incidence or severity of obesity, thereby reducing the incidence or severity of associated co-morbidities.

Another aspect of the disclosure includes pharmaceutical compositions prepared for administration to a subject and which include a therapeutically effective amount of one or more of the compounds disclosed herein. The therapeutically effective amount of a disclosed compound will depend on the route of administration, the species of subject and the physical characteristics of the subject being treated. Specific factors that can be taken into account include disease severity and stage, weight, diet and concurrent medications. The relationship of these factors to determining a therapeutically effective amount of the disclosed compounds is understood by those of skill in the art.

Pharmaceutical compositions for administration to a subject can include at least one further pharmaceutically acceptable additive such as carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Pharmaceutical compositions can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like. The pharmaceutically acceptable carriers useful for these formulations are conventional. Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, Pa., 19th Edition (1995), describes compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed.

In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually contain injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (for example, powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

Pharmaceutical compositions disclosed herein include those formed from pharmaceutically acceptable salts and/or solvates of the disclosed compounds. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Particular disclosed compounds possess at least one basic group that can form acid-base salts with acids. Examples of basic groups include, but are not limited to, amino and imino groups. Examples of inorganic acids that can form salts with such basic groups include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. Basic groups also can form salts with organic carboxylic acids, sulfonic acids, sulfo acids or phospho acids or N-substituted sulfamic acid, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, and, in addition, with amino acids, for example with α-amino acids, and also with methanesulfonic acid, ethanesulfonic acid, 2-hydroxymethanesulfonic acid, ethane-1,2-disulfonic acid, benzenedisulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate or N-cyclohexylsulfamic acid (with formation of the cyclamates) or with other acidic organic compounds, such as ascorbic acid. In particular, suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.

Certain compounds include at least one acidic group that can form an acid-base salt with an inorganic or organic base. Examples of salts formed from inorganic bases include salts of the presently disclosed compounds with alkali metals such as potassium and sodium, alkaline earth metals, including calcium and magnesium and the like. Similarly, salts of acidic compounds with an organic base, such as an amine (as used herein terms that refer to amines should be understood to include their conjugate acids unless the context clearly indicates that the free amine is intended) are contemplated, including salts formed with basic amino acids, aliphatic amines, heterocyclic amines, aromatic amines, pyridines, guanidines and amidines. Of the aliphatic amines, the acyclic aliphatic amines, and cyclic and acyclic di- and tri- alkyl amines are particularly suitable for use in the disclosed compounds. In addition, quaternary ammonium counterions also can be used.

Particular examples of suitable amine bases (and their corresponding ammonium ions) for use in the present compounds include, without limitation, pyridine, N,N-dimethylaminopyridine, diazabicyclononane, diazabicycloundecene, N-methyl-N-ethylamine, diethylamine, triethylamine, diisopropylethylamine, mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, tris(hydroxymethyl)methylamine, N,N-dimethyl-N-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine and N-methyl-D-glucamine. For additional examples of “pharmacologically acceptable salts,” see Berge et al., J. Pharm. Sci. 66:1 (1977).

Compounds disclosed herein can be crystallized and can be provided in a single crystalline form or as a combination of different crystal polymorphs. As such, the compounds can be provided in one or more physical form, such as different crystal forms, crystalline, liquid crystalline or non-crystalline (amorphous) forms. Such different physical forms of the compounds can be prepared using, for example different solvents or different mixtures of solvents for recrystallization. Alternatively or additionally, different polymorphs can be prepared, for example, by performing recrystallizations at different temperatures and/or by altering cooling rates during recrystallization. The presence of polymorphs can be determined by X-ray crystallography, or in some cases by another spectroscopic technique, such as solid phase NMR spectroscopy, IR spectroscopy, or by differential scanning calorimetry.

The pharmaceutical compositions can be administered to subjects by a variety of mucosal administration modes, including by oral, rectal, intranasal, intrapulmonary, or transdermal delivery, or by topical delivery to other surfaces. Optionally, the compositions can be administered by non-mucosal routes, including by intramuscular, subcutaneous, intravenous, intra-arterial, intra-articular, intraperitoneal, intrathecal, intracerebroventricular, or parenteral routes. In other alternative embodiments, the compound can be administered ex vivo by direct exposure to cells, tissues or organs originating from a subject.

To formulate the pharmaceutical compositions, the compound can be combined with various pharmaceutically acceptable additives, as well as a base or vehicle for dispersion of the compound. Desired additives include, but are not limited to, pH control agents, such as arginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, and the like. In addition, local anesthetics (for example, benzyl alcohol), isotonizing agents (for example, sodium chloride, mannitol, sorbitol), adsorption inhibitors (for example, Tween 80 or Miglyol 812), solubility enhancing agents (for example, cyclodextrins and derivatives thereof), stabilizers (for example, serum albumin), and reducing agents (for example, glutathione) can be included. Adjuvants, such as aluminum hydroxide (for example, Amphogel, Wyeth Laboratories, Madison, N.J.), Freund's adjuvant, MPLTM (3-O-deacylated monophosphoryl lipid A; Corixa, Hamilton, Ind.) and IL-12 (Genetics Institute, Cambridge, Mass.), among many other suitable adjuvants well known in the art, can be included in the compositions. When the composition is a liquid, the tonicity of the formulation, as measured with reference to the tonicity of 0.9% (w/v) physiological saline solution taken as unity, is typically adjusted to a value at which no substantial, irreversible tissue damage will be induced at the site of administration. Generally, the tonicity of the solution is adjusted to a value of about 0.3 to about 3.0, such as about 0.5 to about 2.0, or about 0.8 to about 1.7.

The compound can be dispersed in a base or vehicle, which can include a hydrophilic compound having a capacity to disperse the compound, and any desired additives. The base can be selected from a wide range of suitable compounds, including but not limited to, copolymers of polycarboxylic acids or salts thereof, carboxylic anhydrides (for example, maleic anhydride) with other monomers (for example, methyl (meth)acrylate, acrylic acid and the like), hydrophilic vinyl polymers, such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives, such as hydroxymethylcellulose, hydroxypropylcellulose and the like, and natural polymers, such as chitosan, collagen, sodium alginate, gelatin, hyaluronic acid, and nontoxic metal salts thereof. Often, a biodegradable polymer is selected as a base or vehicle, for example, polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyhydroxybutyric acid, poly(hydroxybutyric acid-glycolic acid) copolymer and mixtures thereof. Alternatively or additionally, synthetic fatty acid esters such as polyglycerin fatty acid esters, sucrose fatty acid esters and the like can be employed as vehicles. Hydrophilic polymers and other vehicles can be used alone or in combination, and enhanced structural integrity can be imparted to the vehicle by partial crystallization, ionic bonding, cross-linking and the like. The vehicle can be provided in a variety of forms, including fluid or viscous solutions. gels, pastes, powders, microspheres and films for direct application to a mucosal surface.

The compound can be combined with the base or vehicle according to a variety of methods, and release of the compound can be by diffusion, disintegration of the vehicle, or associated formation of water channels. In some circumstances, the compound is dispersed in microcapsules (microspheres) or nanocapsules (nanospheres) prepared from a suitable polymer, for example, isobutyl 2-cyanoacrylate (see, for example, Michael et al., J. Pharmacy Pharmacol. 43:1-5, 1991), and dispersed in a biocompatible dispersing medium, which yields sustained delivery and biological activity over a protracted time.

The compositions of the disclosure can alternatively contain as pharmaceutically acceptable vehicles substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate. For solid compositions, conventional nontoxic pharmaceutically acceptable vehicles can be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.

Pharmaceutical compositions for administering the compound can also be formulated as a solution, microemulsion, or other ordered structure suitable for high concentration of active ingredients. The vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity for solutions can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of a desired particle size in the case of dispersible formulations, and by the use of surfactants. In many cases, it will be desirable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol and sorbitol, or sodium chloride in the composition. Prolonged absorption of the compound can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.

In certain embodiments, the compound can be administered in a time release formulation, for example in a composition which includes a slow release polymer. These compositions can be prepared with vehicles that will protect against rapid release, for example a controlled release vehicle such as a polymer, microencapsulated delivery system or bioadhesive gel. Prolonged delivery in various compositions of the disclosure can be brought about by including in the composition agents that delay absorption, for example, aluminum monostearate hydrogels and gelatin. When controlled release formulations are desired, controlled release binders suitable for use in accordance with the disclosure include any biocompatible controlled release material which is inert to the active agent and which is capable of incorporating the compound and/or other biologically active agent. Numerous such materials are known in the art. Useful controlled-release binders are materials that are metabolized slowly under physiological conditions following their delivery (for example, at a mucosal surface, or in the presence of bodily fluids). Appropriate binders include, but are not limited to, biocompatible polymers and copolymers well known in the art for use in sustained release formulations. Such biocompatible compounds are non-toxic and inert to surrounding tissues, and do not trigger significant adverse side effects, such as nasal irritation, immune response, inflammation, or the like. They are metabolized into metabolic products that are also biocompatible and easily eliminated from the body.

Exemplary polymeric materials for use in the present disclosure include, but are not limited to, polymeric matrices derived from copolymeric and homopolymeric polyesters having hydrolyzable ester linkages. A number of these are known in the art to be biodegradable and to lead to degradation products having no or low toxicity. Exemplary polymers include polyglycolic acids and polylactic acids, poly(DL-lactic acid-co-glycolic acid), poly(D-lactic acid-co-glycolic acid), and poly(L-lactic acid-co-glycolic acid). Other useful biodegradable or bioerodable polymers include, but are not limited to, such polymers as poly(epsilon-caprolactone), poly(epsilon-aprolactone-CO-lactic acid), poly(epsilon.-aprolactone-CO-glycolic acid), poly(beta-hydroxy butyric acid), poly(alkyl-2-cyanoacrilate), hydrogels, such as poly(hydroxyethyl methacrylate), polyamides, poly(amino acids) (for example, L-leucine, glutamic acid, L-aspartic acid and the like), poly(ester urea), poly(2-hydroxyethyl DL-aspartamide), polyacetal polymers, polyorthoesters, polycarbonate, polymaleamides, polysaccharides, and copolymers thereof. Many methods for preparing such formulations are well known to those skilled in the art (see, for example, Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978). Other useful formulations include controlled-release microcapsules (U.S. Pat. Nos. 4,652,441 and 4,917,893), lactic acid-glycolic acid copolymers useful in making microcapsules and other formulations (U.S. Pat. Nos. 4,677,191 and 4,728,721) and sustained-release compositions for water-soluble peptides (U.S. Pat. No. 4,675,189).

The pharmaceutical compositions of the disclosure typically are sterile and stable under conditions of manufacture, storage and use. Sterile solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the compound and/or other biologically active agent into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein. In the case of sterile powders, methods of preparation include vacuum drying and freeze-drying which yields a powder of the compound plus any additional desired ingredient from a previously sterile-filtered solution thereof. The prevention of the action of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

In accordance with the various treatment methods of the disclosure, the compound can be delivered to a subject in a manner consistent with conventional methodologies associated with management of the disorder for which treatment or prevention is sought. In accordance with the disclosure herein, a prophylactically or therapeutically effective amount of the compound and/or other biologically active agent is administered to a subject in need of such treatment for a time and under conditions sufficient to prevent, inhibit, and/or ameliorate a selected disease or condition or one or more symptom(s) thereof.

The administration of the compound of the disclosure can be for either prophylactic or therapeutic purpose. When provided prophylactically, the compound is provided in advance of any symptom. The prophylactic administration of the compound serves to prevent or ameliorate any subsequent disease process. When provided therapeutically, the compound is provided at (or shortly after) the onset of a symptom of disease or infection.

For prophylactic and therapeutic purposes, the compound can be administered to the subject by the oral route or in a single bolus delivery, via continuous delivery (for example, continuous transdermal, mucosal or intravenous delivery) over an extended time period, or in a repeated administration protocol (for example, by an hourly, daily or weekly, repeated administration protocol). The therapeutically effective dosage of the compound can be provided as repeated doses within a prolonged prophylaxis or treatment regimen that will yield clinically significant results to alleviate one or more symptoms or detectable conditions associated with a targeted disease or condition as set forth herein. Determination of effective dosages in this context is typically based on animal model studies followed up by human clinical trials and is guided by administration protocols that significantly reduce the occurrence or severity of targeted disease symptoms or conditions in the subject. Suitable models in this regard include, for example, murine, rat, avian, dog, sheep, porcine, feline, non-human primate, and other accepted animal model subjects known in the art. Alternatively, effective dosages can be determined using in vitro models. Using such models, only ordinary calculations and adjustments are required to determine an appropriate concentration and dose to administer a therapeutically effective amount of the compound (for example, amounts that are effective to alleviate one or more symptoms of a targeted disease). In alternative embodiments, an effective amount or effective dose of the compound may simply inhibit or enhance one or more selected biological activities correlated with a disease or condition, as set forth herein, for either therapeutic or diagnostic purposes.

The actual dosage of the compound will vary according to factors such as the disease indication and particular status of the subject (for example, the subject's age, size, fitness, extent of symptoms, susceptibility factors, and the like), time and route of administration, other drugs or treatments being administered concurrently, as well as the specific pharmacology of the compound for eliciting the desired activity or biological response in the subject. Dosage regimens can be adjusted to provide an optimum prophylactic or therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental side effects of the compound and/or other biologically active agent is outweighed in clinical terms by therapeutically beneficial effects. A non-limiting range for a therapeutically effective amount of a compound and/or other biologically active agent within the methods and formulations of the disclosure is about 0.01 mg/kg body weight to about 20 mg/kg body weight, such as about 0.05 mg/kg to about 5 mg/kg body weight, or about 0.2 mg/kg to about 2 mg/kg body weight.

Dosage can be varied by the attending clinician to maintain a desired concentration at a target site (for example, the lungs or systemic circulation). Higher or lower concentrations can be selected based on the mode of delivery, for example, trans-epidermal, rectal, oral, pulmonary, intraosseous, or intranasal delivery versus intravenous or subcutaneous or intramuscular delivery. Dosage can also be adjusted based on the release rate of the administered formulation, for example, of an intrapulmonary spray versus powder, sustained release oral versus injected particulate or transdermal delivery formulations, and so forth.

The compounds disclosed herein may also be co-administered with an additional therapeutic agent. Such agents include, but are not limited to, an antidiabetic agent, a cholesterol-lowering agent, an anti-inflammatory agent, an antimicrobial agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound.

The instant disclosure also includes kits, packages and multi-container units containing the herein described pharmaceutical compositions, active ingredients, and/or means for administering the same for use in the prevention and treatment of diseases and other conditions in mammalian subjects. Kits for diagnostic use are also provided. In one embodiment, these kits include a container or formulation that contains one or more of the compounds described herein. In one example, this component is formulated in a pharmaceutical preparation for delivery to a subject. The compound is optionally contained in a bulk dispensing container or unit or multi-unit dosage form. Optional dispensing means can be provided, for example a pulmonary or intranasal spray applicator. Packaging materials optionally include a label or instruction indicating for what treatment purposes and/or in what manner the pharmaceutical agent packaged therewith can be used.

EXAMPLES Illustrative Example 1

To the sulfonyl urea compound 3 (446 mg, 1.00 mmoles) in chlorobenzene 3 mL (Synthesis Scheme 1) was added PCl₅ and the mixture was heated for 1 h. The solvent was then evaporated and the imidoyl chloride residue was dissolved in dichloromethane and treated with a pre-mixed mixture of acetamidine hydrochloride (3.06 mmoles) in methanol:dichloromethane:Et₃N (2:1:1) at −78° C. dropwise and allowed to warm up to room temperature overnight. The reaction mixture was extracted in to dichloromethane washed with water and purified by flash chromatography using hexanes: EtOAC (6:4) to afford the amidino compound A above in 30-40% yield. The characterization data is shown in Table 1.

Illustrative Example 2

To the acid Compound XIII (1.2 mg, 4 mmoles) in dichloromethane Synthesis Scheme 2 was added EDCI (2eq), DMAP (2eq) and 2-napthalene sulfonamide (1.1 eq) ans stirred overnight. The mixture was then acidified with IN HC1 and extracted with water and dichloromethane. The dichloromethane layer was evaporated and the crude residue was triturated with IPA to give the pure sulfonyl urea compound 4 in 40-50 yield based on recovered material. The compound 4 was then taken up in dichloromethane and PC15 and the mixture was heated at reflux for 24 h. The imidoyl chloride residue was dissolved in further dichloromethane and treated with a pre-mixed mixture of methyl carbamimidothioate hydroiodide (2 mmoles) in methanol:dichloromethane:Et₃N (2:1:1) at −78° C. dropwise and allowed to wain up to room temperature overnight. The reaction mixture was extracted in to dichloromethane washed with water and purified by flash chromatography using hexanes: EtOAC (6:4) to afford the amidino compound B above in 50-60% yield. The characterization data is shown in Table 4.

The compounds disclosed herein may have a high affinity for the mouse CB1 receptor in a radioligand displacement assay using mouse brain plasma membranes and ³H-CP55540 as the labeled ligand. For example, compound MRI-1950 has a K_(i)CB1 of 1.2 nM. In addition, the compounds disclosed herein may be less lipophilic. For example, compound MRI-1950 has a CLogP value of 3.3 that makes it less lipophilic, consequently improving its water solubility.

TABLE 1

K_(i) Serial CB1 Mass CLogP/tPSA # R¹ A (nM) H-NMR (400 MHz, CDCl3): MH⁼ (theoretical)  1 Me CH₂  3 δ 7.54 (d, J = 7.5 Hz, 2H), 487.02  3.50/101.22 7.33-7.29 (m, 3H), 7.23-7.21 (m, 2H), 7.15 (d, J = 6.5 Hz, 2H), 4.71-4.69 (m, 1H), 4.49- 4.43 (m, 1H), 4.04-4.00 (m, 1H), 3.12 (d, J = 0.7 Hz, 4H), 2.11 (s, 3H), 1.63 (t, J = 0.8 Hz, 5H), 1.46 (d, J = 0.7 Hz, 2H).  2 CH₃CONH CH₂ 1.6 δ 7.65-7.63 (m, 2H), 7.31 530.04  3.96/130.32 (d, J = 7.0 Hz, 3H), 7.22-7.16 (m, 2H), 7.15 (d, J = 7.2 Hz, 2H), 4.62 (s, 2H), 3.93 (s, 1H), 3.11 (m, 4H), 1.94 (s, 3H), 1.69 (d, J = 2.8 Hz, 4H), 1.49 (s, 2H).  3 SMe CH₂ 15 δ 7.58 (s, 2H), 7.35-7.31 (m, 519.08  4.39/101.22 2H), 7.29 (s, 1H), 7.21 (dd, J = 13.8, 7.2 Hz, 4H), 4.70- 4.66 (m, 1H), 4.52-4.46 (m, 1H), 4.05-4.02 (m, 1H), 3.13 (m, 4H), 2.52 (s, 3H), 1.65 (m, 4H), 1.47 (s, 2H).  4 t-Butyl CH₂ 23 δ 7.52 (s, 2H), 7.32 (d, J = 529.1  4.74/101.22 6.7 Hz, 3H), 7.23-7.21 (m, 2H), 7.17 (s, 2H), 4.94 (s, 1H), 4.69-4.67 (m, 1H), 4.50- 4.44 (m, 1H), 4.01-3.98 (m, 1H), 3.13 (m, 4H), 1.63 (t, J = 1.0 Hz, 4H), 1.47 (s, 2H), 1.36 (s, 9H).  5 4-F-phenyl CH₂ δ 7.85 (s, 2H), 7.47-7.46 (m, 567  6.43/101/22 2H), 7.21 (d, J = 5.0 Hz, 5H), 7.06 (t, J = 8.1 Hz, 2H), 6.60-6.59 (m, 2H), 6.30-6.28 (bs, 2H), 4.52-4.49 (m, 1H), 4.33-4.30 (m, 1H), 3.79 (s, 1H), 3.16 (s, 4H), 1.66 (s, 4H), 1.48 (s, 2H).  6 4-Cl-phenyl CH₂ δ 7.77 (d, J = 7.8 Hz, 2H), 583.5  7.00/101.22 7.46-7.44 (m, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.9 Hz, 5H), 6.59-6.58 (m, 2H), 6.25 (s, 2), 4.50 (dt, J = 9.3, 0.9 Hz, 1H), 4.31-4.29 (m, 1H), 3.79-3.75 (m, 1H), 3.15 (m, 4H), 1.66 (m, 4H), 1.48 (s, 2H).  7 Me CF₂ δ 7.54 (d, J = 7.6 Hz, 2H), 523.00  2.89/101.22 7.31 (t, J = 7.3 Hz, 3H), 7.23 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 6.9 Hz, 2H), 5.39 (s, 1H), 4.72-4.70 (m, 1H), 4.43 (t, J = 12.1 Hz, 1H), 4.01-3.97 (m, 1H), 3.33 (m, 4H), 2.10 (d, J = 14.0 Hz, 7H).  8 CH₃CONH CF₂ 1.2 δ 7.63-7.61 (m, 2H), 7.32 (d, 566.02  3.34/130.32 J = 6.9 Hz, 2H), 7.31-7.28 (m, 1H), 7.22 (s, 2H), 7.16 (d, J = 7.0 Hz, 2H), 4.66-4.64 (m, 1H), 4.55-4.49 (m, 1H), 3.97 (t, J = 5.8 Hz, 1H), 3.33 (m, 4H), 2.05 (m, 7H).  9 SMe CF₂ 14 δ 7.58 (s, 2H), 7.33 (d, J = 555.06  3.77/101.22 7.1 Hz, 4H), 7.23-7.17 (m, 3H), 4.70 (dddd, J = 5.5, 4.1, 2.6, 1.4 Hz, 1H), 4.50-4.45 (m, 1H), 4.02 (ddd, J = 5.3, 2.6, 1.6 Hz, 1H), 3.35 (m, 4H), 2.52 (s, 3H), 2.10 (s, mH). 10 t-Butyl CF₂ 21 δ 7.51 (s, 2H), 7.32 (q, J = 565.08 41.2/101.22 7.6 Hz, 3H), 7.19 (dd, J = 26.8, 7.1 Hz, 4H), 4.94 (s, 1H), 4.71-4.68 (m, 1H), 4.44 (t, J = 11.4 Hz, 1H), 3.99- 3.95 (m, 1H), 3.35 (m, 4H), 2.08 (s, mH), 1.37 (s, 9H). 11 4-F-phenyl CF₂ δ 7.85 (dd, J = 7.0, 5.2 Hz, 603.06  5.82/101.22 2H), 7.46 (td, J = 1.8, 1.1 Hz, 2H), 7.23 (m, 5H), 7.09 (t, J = 8.2 Hz, 2H), 6.60 (dt, J = 2.0, 1.3 Hz, 2H), 6.03-5.99 (m, 2H), 4.52 (td, J = 3.7, 2.6 Hz, 1H), 4.31-4.27 (m, 1H), 3.79-3.76 (m, 1H), 3.37 (m, 4H), 2.10 (m, 4H). 12 4-Cl-phenyl CF₂ δ 7.77 (d, J = 8.1 Hz, 2H), 619.5  6.57/101.22 7.46-7.44 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 7.9 Hz, 5H), 6.57 (s, 2H), 6.11 (s, 2H), 4.53-4.50 (m, 1H), 4.28 (t, J = 6.6 Hz, 1H), 3.76-3.74 (m, 1H), 3.37 (d, J = 0.9 Hz, 4H), 2.10 (m, 4H). 13 Me CH  3 δ 7.54 (d, J = 7.6 Hz, 2H), 555.02  3.59/101.22 CF₃ 7.33-7.29 (m, 3H), 7.23 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.1 Hz, 2H), 5.34 (s, 1H), 4.70-4.69 (m, 1H), 4.47-4.41 (m, 1H), 4.01-3.97 (m, 1H), 3.86 (m, 2H), 2.63-2.60 (m, 2H), 2.11 (s, 3H), 2.04 (s, 1H), 1.86 (m, 2H), 1.74-1.71 (m, 2H). 14 CH₃CONH CH δ 7.62 (dt, J = 4.3, 2.1 Hz, 598.04  4.05/130.32 CF₃ 2H), 7.33-7.29 (m, 3H), 7.26- 7.21 (m, 3H), 7.17-7.15 (m, 1H), 4.68-4.64 (m, 1H), 4.56- 4.49 (m, 1H), 3.99-3.95 (m, 1H), 3.88-3.84 (m, 2H), 2.58- 2.52 (m, 2H), 2.10 (d, J = 0.6 Hz, 4H), 1.92-1.84 (m, 2H), 1.77-1.70 (m, 2H). 15 SMe CH δ 7.57 (s, 2H), 7.31 (t, J = 587.08  4.48/101.22 CF₃ 8.0 Hz, 3H), 7.23 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 6.1 Hz, 2H), 5.33 (s, 1H), 4.72-4.68 (m, 1H), 4.49-4.46 (m, 1H), 4.02-3.99 (m, 1H), 3.86-3.84 (m, 2H), 2.65-2.53 (m, 5H), 2.08-2.04 (m, 1H), 1.91-1.88 (m, 2H), 1.75-1.72 (m, 2H). 16 t-Butyl CH δ 7.52 (s, 2H), 7.33-7.29 (m, 597.10  4.83/101.22 CF₃ 3H), 7.23 (d, J = 8.5 Hz, 2H), 7.15 (t, J = 0.7 Hz, 2H), 4.93 (s, 2H), 4.71-4.67 (m, 1H), 4.47-4.41 (m, 1H), 4.00-3.96 (m, 1H), 3.88-3.85 (m, 2H), 2.64-2.59 (m, 2H), 2.04 (s, 1H), 1.90-1.86 (m, 2H), 1.75- 1.71 (m, 2H), 1.37 (s, 9H). 17 Me O δ 7.54 (d, J = 7.7 Hz, 2H), 488.99  3.21/110.45 7.35-7.29 (m, 3H), 7.15 (d, J = 6.7 Hz, 4H), 5.28 (s, 1H), 4.77-4.69 (m, 1H), 4.49-4.38 (m, 1H), 4.03-3.99 (m, 1H), 3.75 (m, 4H), 3.16-3.11 (m, 4H), 2.11 (s, 3H). 18 SMe O δ 7.59 (s, 2H), 7.32 (d, J = 521.06  3.83/110.45 6.9 Hz, 3H), 7.24-7.18 (m, 4H), 4.71-4.69 (m, 1H), 4.52- 4.47 (m, 1H), 4.06-4.00 (m, 1H), 3.77 (m, 4H), 3.17 (m, 4H), 2.52 (s, 3H). 19* 4-F-phenyl CH δ 7.82 (dd, J = 8.7, 5.3 Hz, 636.08  6.5/101.2 CF₃ 2H), 7.46-7.44 (m, 2H), 7.25- 7.19 (m, 5H), 7.04 (t, J = 8.6 Hz, 2H), 6.57 (s, 2H), 6.43 (s, 2H), 4.51-4.48 (m, 1H), 4.30-4.25 (m, 1H), 3.87 (t, J = 10.3 Hz, 2H), 3.79-3.75 (m, 1H), 2.69-2.59 (m, 2H), 2.07 (d, J = 16.0 Hz, 1H), 1.90 (d, J = 13.0 Hz, 2H), 1.78-1.70 (m, 2H). 20 4-Cl-phenyl CH δ 7.77 (d, J = 8.4 Hz, 2H), 651.53  7.2/101.22 CF₃ 7.46-7.45 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.22 (t, J = 6.1 Hz, 5H), 6.63 (s, 2H), 5.97 (s, 2H), 4.55-4.51 (m, 1H), 4.33-4.27 (m, 1H), 3.92- 3.86 (m, 2H), 3.79-3.75 (m, 1H), 2.69-2.59 (m, 2H), 2.08- 2.05 (m, 1H), 1.89 (d, J = 8.1 Hz, 2H), 1.79-1.71 (m, 2H). 21 4-F-phenyl O δ 7.85 (dd, J = 8.3, 5.4 Hz, 569.05  5.62/110.4 2H), 7.50 (d, J = 25.1 Hz, 2H), 7.22-7.20 (m, 5H), 7.07 (t, J = 8.4 Hz, 2H), 6.63 (s, 2H), 6.09-6.06 (m, 2H), 4.54- 4.51 (m, 1H), 4.36-4.30 (m, 1H), 3.84-3.82 (m, 5H), 3.19 (s, 4H). 22 4-Cl-phenyl O δ 7.75 (t, J = 8.8 Hz, 2H), 7.45-7.37 (m, 2H), 7.37-7.32 (m, 2H), 7.23 (t, J = 9.7 Hz, 5H), 6.58 (s, 2H), 6.20 (s, 2H), 4.52-4.50 (m, 1H), 4.32- 4.28 (m, 1H), 3.76 (s, 5H), 3.18 (s, 4H). 585.5  6.19/110.4 23 CH₃CONH O δ 7.63 (d, J = 8.3 Hz, 2H), 532.02  3.53/139.5 7.31 (q, J = 7.9 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 3H), 4.66 (dd, J = 11.5, 5.8 Hz, 1H), 4.52 (t, J = 11.8 Hz, 1H), 4.00 (dd, J = 12.0, 5.9 Hz, 1H), 3.76 (d, J = 3.4 Hz, 4H), 3.18 (d, J = 3.2 Hz, 4H), 2.09 (s, 3H). 24 t-Butyl O δ 7.53 (s, 2H), 7.32 (t, J = 531.07  4.4/110.4 7.2 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.16 (d, J= 7.2 Hz, 2H), 4.68 (dd, J = 11.5, 5.5 Hz, 1H), 4.46 (t, J = 11.9 Hz, 1H), 4.00 (dd, J = 12.1, 5.5 Hz, 1H), 3.75 (s, 4H), 3.17 (s, 4H), 1.35 (s, 9H). 25 SMe CH δ 7.59-7.58 (m, 2H), 7.30 595.1  5.8/101.2 Ph (dd, J = 17.9, 7.4 Hz, 3H), 7.21 (dd, J = 14.7, 8.1 Hz, 4H), 4.70 (dd, J = 11.5, 5.4 Hz, 1H), 4.51 (t, J = 11.8 Hz, 1H), 4.05 (dd, J = 12.1, 5.2 Hz, 1H), 3.92-3.87 (m, 2H), 2.76-2.67 (m, 2H), 2.53 (s, 3H), 1.88 (d, J = 3.4 Hz, 3H). 26 Me CH Ph 563.11  4.9/101.22

TABLE 2

K_(i) Serial CB₁ CLogP/tPSA # R¹ R² R³ (nM) H-NMR Mass (theoretical) 1 Me Et Et δ 7.53 (d, J = 8.5 Hz, 2H), 475.16 2.67/101.22 7.30 (q, J = 7.5 Hz, 3H), 7.21 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 7.0 Hz, 2H), 5.34 (s, 1H), 4.67 (dd, J = 11.6, 5.3 Hz, 1H), 4.42 (t, J = 12.0 Hz, 1H), 3.99 (dd, J = 12.3, 5.3 Hz, 1H), 3.25 (q, J = 7.3 Hz, 4H), 2.10 (s, 3H), 1.18 (dt, J = 13.9, 6.8 Hz, 7H) 2 SMe Et Et δ 7.57 (s, 2H), 7.32-7.31 (m, 508.08 3.74/101.22 3H), 7.22 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 5.8 Hz, 2H), 4.69-4.65 (m, 1H), 4.49-4.43 (m, 1H), 4.04-3.99 (m, 1H), 3.26 (d, J = 6.7 Hz, 4H), 2.52 (s, 3H), 1.19 (m, 6H). 3 t-Butyl Et Et δ 7.51 (d, J = 8.3 Hz, 2H), 517.09 3.91/101.22 7.29 (t, J = 8.3 Hz, 3H), 7.21 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 7.2 Hz, 2H), 4.65 (dd, J = 11.6, 5.6 Hz, 1H), 4.42 (t, J = 11.9 Hz, 1H), 3.97 (dd, J = 12.2, 5.6 Hz, 1H), 3.25 (q, J = 7.1 Hz, 4H), 1.36 (s, 9H), 1.17 (t, J = 7.1 Hz, 6H). 4 CH₃CONH Et Et δ 8.50 (s, 1H), 7.61 (d, J = 518.03 3.31/130.3 8.3 Hz, 2H), 7.30-7.25 (m, 3H), 7.21 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 7.1 Hz, 2H), 4.63 (dd, J = 11.0, 5.4 Hz, 1H), 4.52- 4.46 (m, 1H), 4.01-3.97 (m, 1H), 3.24 (q, J = 7.1 Hz, 4H), 2.09 (s, 3H), 1.19 (t, J = 7.2 Hz, 6H). 5 4-F-phenyl Et Et δ 7.89 (dd, J = 8.6, 5.3 Hz, 555.07 5.7/101.22 2H), 7.49-7.47 (m, 2H), 7.22- 7.19 (m, 5H), 7.10 (t, J = 8.6 Hz, 2H), 6.78 (s, 2H), 5.6 (bs, 1H), 4.56-4.52 (m, 1H), 4.37- 4.30 (m, 1H), 3.89-3.86 (m, 1H), 3.28 (q, J = 7.1 Hz, 4H), 1.19 (t, J = 7.1 Hz, 6H). 6 4-Cl-phenyl Et Et δ 7.79 (d, J = 8.3 Hz, 2H), 571.5 6.35/101.22 7.47-7.45 (m, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.21 (t, J = 7.0 Hz, 5H), 6.68 (s, 2H), 6.00 (s, 2H), 4.53-4.49 (m, 1H), 4.33- 4.27 (m, 1H), 3.82-3.77 (m, 1H), 3.28 (q, J = 7.1 Hz, 4H), 1.19 (dd, J = 8.8, 6.0 Hz, 6H). 7 t-Butyl i-Pr i-pr 545.1 4.5/101.22

TABLE 3

K_(i) Serial CB₁ CLogP/tPSA # R¹ A (nM) H-NMR Mass (theoretical) 1 Me CH₂ δ 7.52 (s, 2H), 7.33-7.26 (m, 3H), 473 2.94/101.22 7.22 (d, J = 8.6 Hz, 2H), 7.15 (s, 2H), 5.21 (s, 2H), 4.68 (ddd, J = 11.5, 5.3, 0.3 Hz, 1H), 4.46-4.40 (m, 1H), 4.01-3.97 (m, 1H), 3.33- 3.30 (m, 4H), 2.11 (s, 3H), 1.85- 1.82 (m, 4H). 2 SMe CH₂ δ 7.57 (s, 2H), 7.32 (dd, J = 6.7, 505.06 3.83/101.22 0.8 Hz, 3H), 7.23 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 4.68 (d, J = 9.6 Hz, 1H), 4.49-4.43 (m, 1H), 4.01 (d, J = 16.1 Hz, 1H), 3.34 (m, 4H), 2.53 (s, 3H), 1.86 (m, 4H). 3 4-F-phenyl CH₂ ¹H-NMR (400 MHz, CDCl₃): δ 553.05 5.87/101.22 7.88 (dd, J = 8.3, 5.4 Hz, 2H), 7.47 (d, J = 7.4 Hz, 2H), 7.21 (d, J = 8.5 Hz, 5H), 7.08 (t, J = 8.4 Hz, 2H), 6.70 (s, 2H), 5.94 (s, 2H), 4.54-4.50 (m, 1H), 4.35-4.28 (m, 1H), 3.84- 3.80 (m, 1H), 3.35 (d, J = 5.7 Hz, 4H), 1.86 (s, 4H). 4 4-Cl-phenyl CH₂ H-NMR (400 MHz, CDCl₃): δ 7.79 569.51 6.4/101.2 (d, J = 8.4 Hz, 2H), 7.50-7.41 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 6.5 Hz, 5H), 6.64 (s, 2H), 6.13 (s, 2H), 4.52-4.49 (m, 1H), 4.34-4.26 (m, 1H), 3.81-3.75 (m, 1H), 3.35 (d, J = 6.8 Hz, 4H), 1.86 (s, 4H). 5 CH₃CONH CH₂ 516.02 3.4/130.3 6 t-Butyl CH₂ δ 7.52-7.50 (m, 2H), 7.31 (q, J = 515.07 4.18/101.2 7.8 Hz, 4H), 7.21 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 7.3 Hz, 2H), 4.66 (dd, J = 11.7, 5.6 Hz, 1H), 4.43 (t, J = 12.0 Hz, 1H), 3.98 (dd, J = 12.2, 5.6 Hz, 1H), 3.32 (t, J = 6.3 Hz, 4H), 1.84 (t, J = 6.3 Hz, 4H), 1.36 (s, 9H).

TABLE 4

K_(i) Serial CB₁ CLogP/tPSA # R¹ R¹² (nM) H-NMR Mass (theoretical) 1 4-Cl-phenyl Fused Ph— 626.5 9.8/97.9 2 SMe Fused Ph 8.51 (s, 1H), 7.94- 562 7.7/97.9 7.87 (m, 3H), 7.58 (t, J = 8.4 Hz, 2H), 7.28 (t, J = 5.2 Hz, 6H), 7.12-7.07 (m, 3H), 6.92 (d, J = 8.9 Hz, 2H), 5.70 (s, 2H), 5.37 (dd, J = 13.1, 6.6 Hz, 1H), 3.75 (dd, J = 17.9, 13.1 Hz, 1H), 3.12-3.06 (m, 1H), 2.21 (s, 3H). 3 4-F-phenyl Fused Ph— 610.1 9.3/97.9 4 Me Fused Ph 528.02 6.17/97.9 5 t-Butyl Fused Ph 570.1 7.4/97.9 6 CH₃CONH Fused Ph 571.05 5.74/127.08 7 SMe CF₃ 580.04 7.43/97.9 8 t-Butyl CF₃ 590.06 7.7/97.9 9 SMe Cl 546.5 7.2/97.9

Several embodiments are described below in the following numbered clauses:

1. A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy;

R¹, R², and R³ are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, aralkyl, optionally-substituted thiol, or R² and R³ together with Z form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring;

Z is B, N, —CH—, or P;

D is —S(O)₂— or —C(O)—; and

n is 0 to 5.

2. The compound of clause 1, wherein R² and R³ together with Z do not form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring.

3. The compound of clause 2, wherein R² and R³ are each independently optionally-substituted alkyl.

4. The compound of clause 3, wherein R² and R³ are each the same and are each lower alkyl, and Z is N.

5. The compound of clause 1, wherein the compound has a structure of:

wherein R²⁵ is an optionally-substituted N-heterocycle.

6. The compound of any one of clauses to 1 to 5, wherein each of X and Y is an optionally-substituted aryl.

7. The compound of clause 5, wherein the compound has a structure of:

wherein each of R⁴, R¹⁰ and R¹¹ is independently selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, or optionally-substituted phosphinyl;

A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, mono or di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono or di-substituted C-aryl, mono or di-substituted C-cycloalkyl, —CH(COOR²⁰)—, —CH(CN)—, —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ is H or alkyl;

a and b are each 0 to 5; and

c is 0 to 7.

8. The compound of clause 7, wherein the compound has a structure of:

9. The compound of clause 8, wherein the compound has a structure of:

10. The compound of clause 7, wherein the compound has a structure of:

11. The compound of clause 10, wherein the compound has a structure of:

12. A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl;

Q is H, hydroxyl, or optionally-substituted alkoxy; and

U is

wherein R^(a) —C(═NH)R¹, wherein R¹ is H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, or optionally-substituted phosphinyl; and R^(b) is a substituted sulfonyl or a substituted carbonyl.

13. The compound of clause 12. wherein the compound has a structure of:

wherein R², and R³ are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, or R² and R³ together with Z form an optionally-substituted cycloalkyl ring, an optionally-substituted heterocycloalkyl ring; an optionally-substituted aryl ring, or an optionally-substituted heteroaryl ring;

Z is B, N, —CH—, or P; and

n is 0 to 5.

14. The compound of clause 13, wherein R² and R³ together with Z do not form an optionally-substituted cycloalkyl ring, an optionally-substituted heterocycloalkyl ring; an optionally-substituted aryl ring, or an optionally-substituted heteroaryl ring.

15. The compound of clause 13, R² and R³ are each independently optionally-substituted alkyl (particularly lower alkyl).

16. The compound of clause 15, wherein R² and R³ are each the same and are each lower alkyl, and Z is N.

17. The compound of clause 13, wherein the compound has a structure of:

wherein each R¹² is independently selected from optionally-substituted alkyl, optionally-substituted heteroalkyl, hydroxy, optionally-substituted alkoxy or optionally-substituted alkylamino, optionally-substituted aryl, halogen, cyano, nitro, acyl or carbonyl; and d is 0 to 5.

18. The compound of clause 13, wherein the compound has a structure of:

wherein R²⁵ is an optionally-substituted N-heterocycle.

19. The compound of clause 18, wherein the compound has a structure of:

wherein each of R¹³, R¹⁴ and R¹⁵ is independently selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, or optionally-substituted phosphinyl;

A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, mono or di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono or di-substituted C-aryl, mono or di-substituted C-cycloalkyl, —CH(COOR²⁰)—, —CH(CN)—, —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ is H or alkyl;

f and g are each 0 to 5; and

g is 0 to 7.

20. The compound of clause 19, wherein the compound has a structure of:

21. The compound of clause 20, wherein the compound has a structure of:

22. The compound of clause 19, wherein the compound has a structure of:

23. The compound of clause 22, wherein the compound has a structure of:

24. The compound of any one of clauses 1 to 23, wherein R¹ is optionally-substituted alkyl (e.g., lower alkyl, thiol-substituted lower alkyl), aminocarbonyl acetamido), or optionally-substituted phenyl (e.g., halogen-substituted phenyl).

25. The compound of any one of clauses 1 to 24, wherein Q is H.

26. The compound of any one of clauses 1 to 25, wherein A is —CH₂—, —CF₂—, —O—, or —CH(CF₃)—.

27. A pharmaceutical composition comprising a compound of any one of clauses 1 to 26, and at least one pharmaceutically acceptable additive.

28. A pharmaceutical composition comprising a unit dosage form of a therapeutic amount of a compound of any one of clauses 1 to 26, and at least one pharmaceutically acceptable additive.

29. A method for treating obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, a co-morbidity of obesity, dyslipidemias that predispose to arteriosclerotic heart disease, diabetic nephropathy, or gout, in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of clauses 1 to 26.

30. The method of claim 29, comprising treating obesity in the subject.

31. The method of claim 29, comprising treating diabetes in the subject.

32. A method of preventing or reversing the deposition of adipose tissue in a subject, comprising administering to the subject in need thereof an effective amount of a compound of any one of clauses 1 to 26.

33. The method of any one of clauses 29 to 32, wherein administering of the compound causes substantially no adverse neuropsychiatric effects.

34. The method of any one of clauses 29 to 34, wherein administering of the compound results in a ratio of maximum concentration in the brain to maximum concentration in plasma which is less than 0.1

In view of the many possible embodiments to which the principles of the disclosed compounds, compositions and methods may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. 

1. A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl; Q is H, hydroxyl, or optionally-substituted alkoxy; R¹, R², and R³ are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, aralkyl, optionally-substituted thiol, or R² and R³ together with Z form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring; Z is B, N, —CH—, or P; D is —S(O)₂— or —C(O)—; and n is 0 to
 5. 2. The compound of claim 1, wherein R² and R³ together with Z do not form an optionally-substituted cycloalkyl ring or an optionally-substituted heterocycloalkyl ring.
 3. The compound of claim 2, wherein R² and R³ are each independently optionally-substituted alkyl.
 4. The compound of claim 3, wherein R² and R³ are each the same and are each lower alkyl, and Z is N.
 5. The compound of claim 1, wherein the compound has a structure of:

wherein R²⁵ is an optionally-substituted N-heterocycle.
 6. The compound of claim 1, wherein each of X and Y is an optionally-substituted aryl.
 7. The compound of claim 5, wherein the compound has a structure of:

wherein each of R⁴, R¹⁰ and R¹¹ is independently selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, or optionally-substituted phosphinyl; A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, mono or di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono or di-substituted C-aryl, mono or di-substituted C-cycloalkyl, —CH(COOR²⁰)—, —CH(CN)—, —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ is H or alkyl; a and b are each 0 to 5; and c is 0 to
 7. 8. The compound of claim 7, wherein the compound has a structure of:


9. The compound of claim 8, wherein the compound has a structure of:


10. The compound of claim 7, wherein the compound has a structure of:


11. The compound of claim 10, wherein the compound has a structure of:


12. A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

wherein X and Y are each independently selected from optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted cycloalkyl, optionally-substituted heterocycloalkyl, or optionally-substituted alkyl; Q is H, hydroxyl, or optionally-substituted alkoxy; and U is

wherein R^(a) —C(═NH)R¹, wherein R¹ is H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, aminocarbonyl, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, or optionally-substituted phosphinyl; and R^(b) is a substituted sulfonyl or a substituted carbonyl.
 13. The compound of claim 12, wherein the compound has a structure of:

wherein R², and R³ are each independently selected from H, optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, optionally-substituted phosphinyl, or R² and R³ together with Z form an optionally-substituted cycloalkyl ring, an optionally-substituted heterocycloalkyl ring; an optionally-substituted aryl ring, or an optionally-substituted heteroaryl ring; Z is B, N, —CH—, or P; and n is 0 to
 5. 14. The compound of claim 13, wherein R² and R³ together with Z do not form an optionally-substituted cycloalkyl ring, an optionally-substituted heterocycloalkyl ring; an optionally-substituted aryl ring, or an optionally-substituted heteroaryl ring.
 15. The compound of claim 13, R² and R³ are each independently optionally-substituted alkyl (particularly lower alkyl).
 16. The compound of claim 15, wherein R² and R³ are each the same and are each lower alkyl, and Z is N.
 17. The compound of claim 13, wherein the compound has a structure of:

wherein each R¹² is independently selected from optionally-substituted alkyl, optionally-substituted heteroalkyl, hydroxy, optionally-substituted alkoxy or optionally-substituted alkylamino, optionally-substituted aryl, halogen, cyano, nitro, acyl or carbonyl; and d is 0 to
 5. 18. The compound of claim 13, wherein the compound has a structure of:

wherein R²⁵ is an optionally-substituted N-heterocycle.
 19. The compound of claim 18, wherein the compound has a structure of:

wherein each of R¹³, R¹⁴ and R¹⁵ is independently selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, halogen, cyano, nitro, hydroxy, optionally-substituted alkoxy, amino, optionally-substituted sulfonyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted carboxyl, acyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted phosphonyl, or optionally-substituted phosphinyl; A is —CH₂—, —O—, —CH(CF₃)—, —CF₂—, —CCl₂—, —N(alkyl)-, —N(aryl)-, mono or di-substituted C-heteroalkyl, mono or di-substituted C-alkyl, mono or di-substituted C-aryl, mono or di-substituted C-cycloalkyl, —CH(COOR²⁰)—, —CH(CN)—, —S—, —S(O)—, —S(O₂)—, or —N(O)—, wherein R²⁰ is H or alkyl; f and g are each 0 to 5; and g is 0 to
 7. 20. The compound of claim 19, wherein the compound has a structure of:


21. The compound of claim 20, wherein the compound has a structure of:


22. The compound of claim 19, wherein the compound has a structure of:


23. The compound of claim 22, wherein the compound has a structure of:


24. The compound of claim 1, wherein R¹ is optionally-substituted alkyl (e.g., lower alkyl, thiol-substituted lower alkyl), aminocarbonyl (e.g., acetamido), or optionally-substituted phenyl (e.g., halogen-substituted phenyl).
 25. The compound of claim 1, wherein Q is H.
 26. The compound of claim 1, wherein A is —CH₂—, —CF₂—, —O—, or —CH(CF₃)—.
 27. The compound of claim 1, wherein D is —S(O)₂—.
 28. The compound of claim 1, wherein n is
 0. 29. The compound of claim 1, wherein X and Y are each optionally-substituted phenyl, and Q is H.
 30. The compound of claim 1, wherein the —NH—C(NH)R¹— moiety or —N═C(NH₂)R¹— moiety comprises a therapeutic scaffold selected from an antidiabetic agent, an anticancer agent, an antiobesity agent, and an antifibrotic agent.
 31. The compound of claim 1, wherein the —NH—C(NH)R¹— moiety or —N═C(NH₂)R¹— moiety comprises a diagnostic agent.
 32. A pharmaceutical composition comprising a compound of claim 1, and at least one pharmaceutically acceptable additive.
 33. A pharmaceutical composition comprising a unit dosage form of a therapeutic amount of a compound of claim 1, and at least one pharmaceutically acceptable additive.
 34. A method for treating obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, a co-morbidity of obesity, dyslipidemias that predispose to arteriosclerotic heart disease, diabetic nephropathy, or gout, in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of claim
 1. 35. The method of claim 34, comprising treating obesity in the subject.
 36. The method of claim 34, comprising treating diabetes in the subject.
 37. A method of preventing or reversing the deposition of adipose tissue in a subject, comprising administering to the subject in need thereof an effective amount of a compound of claim
 1. 38. The method of claim 34, wherein administering of the compound causes substantially no adverse neuropsychiatric effects.
 39. The method of claim 34, wherein administering of the compound results in a ratio of maximum concentration in the brain to maximum concentration in plasma which is less than 0.1. 